Aralkyl diazabicycloalkane derivatives for CNS disorders

ABSTRACT

Certain aralkyl diazabicyloalkyl compounds are described for treatment of CNS disorders such as cerebral ischemia, psychoses and convulsions. Compounds of particular interest are of the formula: ##STR1## wherein: each of R 1 , R 4 , R 5 , R 6  and R 7  is independently selected from the group consisting of hydrido, loweralkyl, benzyl and haloloweralkyl; 
     each of R 2 , R 3 , and R 8  through R 11  is independently selected from the group consisting of hydrido, hydroxy, loweralkyl, benzyl, phenoxy, benzyloxy and haloloweralkyl; 
     n is an integer of from three to four; 
     m is an integer of two; 
     A is selected from the group consisting of phenyl, naphthyl, benzothienyl, benzofuranyl and thienyl and wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from the group consisting of hydrido, hydroxy, loweralkyl, loweralkoxy, halo, haloloweralkyl, amino, monoloweralkylamino and diloweralkylamino; 
     or a pharmaceutically acceptable salt thereof.

FIELD OF THE INVENTION

This is a continuation of application Ser. No. 08/259,203 filed Jun. 13,1994, abandoned which is a continuation of Ser. No. 07/950,358, filedSep. 24, 1992 abandoned.

This invention is in the field of clinical neurology and relatesspecifically to a class of therapeutically useful compounds,compositions and methods for treatment of central nervous system (CNS)dysfunctions, neurotoxic damage, or neurodegenerative diseases. Forexample, these compounds are particularly useful for treating neurotoxicinjury which follows periods of hypoxia, anoxia or ischemia associatedwith stroke, cardiac arrest or perinatal asphyxia. These compounds arealso useful as antipsychotics and anticonvulsants.

BACKGROUND OF THE INVENTION

Unlike other tissues which can survive extended periods of hypoxia,brain tissue is particularly sensitive to deprivation of oxygen orenergy. Permanent damage to neurons can occur during brief periods ofhypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused oraccelerated by certain excitatory amino acids (EAA) found naturally inthe central nervous system (CNS). Glutamate (Glu) is an endogenous aminoacid which has been characterized as a fast excitatory transmitter inthe mammalian brain. Glutamate is also known as a powerful neurotoxincapable of killing CNS neurons under certain pathological conditionswhich accompany stroke and cardiac arrest. Normal glutamateconcentrations are maintained within brain tissue by energy-consumingtransport systems. Under low energy conditions which occur duringconditions of hypoglycemia, hypoxia or ischemia, cells can releaseglutamate. Under such low energy conditions the cell is not able to takeglutamate back into the cell. Initial glutamate release stimulatesfurther release of glutamate which results in an extracellular glutamateaccumulation and a cascade of neurotoxic injury.

It has been shown that the sensitivity of central neurons to hypoxia andischemia can be reduced by either blockage of synaptic transmission orby the specific antagonism of postsynaptic glutamate receptors see S. M.Rothman and J. W. Olney, "Glutamate and the Pathophysiology ofHypoxia-Ischemic Brain Damage," Annals of Neurology, 19, No. 2 (1986)!.Glutamate is characterized as a broad spectrum agonist having activityat three neuronal excitatory amino acid receptor sites. These receptorsites are named after the amino acids which selectively excite them,namely: Kainate (KA), N-methyl-D-aspartate (NMDA or NMA) and quisqualate(QUIS).

Neurons which have EAA receptors on their dendritic or somal surfacesundergo acute excitotoxic degeneration when these receptors areexcessively activated by glutamate. Thus, agents which selectively blockor antagonize the action of glutamate at the EAA synaptic receptors ofcentral neurons can prevent neurotoxic injury associated with hypoxia,anoxia, or ischemia caused by stroke, cardiac arrest or perinatalasphyxia.

It is known that compounds of various structures, such asaminophosphonovalerate derivatives and piperidine dicarboxylatederivatives, may act as competitive antagonists at the NMDA receptor.Certain piperidineethanol derivatives, such as ifenprodil and1-(4-chlorophenyl)-2- 1-(4-fluorophenyl)-piperidinyl!ethanol, which areknown anti-ischemic agents, have been found to be non-competitive NMDAreceptor antagonists C. Carter et al, J. Pharm Exp. Ther., 247 (3),1222-1232 (1988)!.

There are many classes of compounds known for treatment of psychoticdisorders. For example, current therapeutic treatments for psychoses usecompounds classifiable as phenothiazine-thioxanthenes, asphenylbutylpiperidines and also as certain alkaloids. An example of aphenylbutylpiperidine compound of current use in psychotic treatmenttherapy is haloperidol A. F. Gilman et al, The Pharmacological Basis ofTherapeutics, 7th Edn., p. 404, MacMillan (1985)!.

Certain nitrogen-containing cyclohetero cycloalkylaminoaryl compoundsare known for pharmaceutical purposes. For example, U.S. Pat. No.4,204,003 to Szmuszkovicz describesN-(2-aminocyclopentyl)-N-alkanoylanilides as antidepressant agents.

Certain aminocycloaliphatic benzamides have been described for varioususes. For example, U.S. Pat. No. 4,463,013 to Collins et al describesaminocyclohexyl-benzamides for use as diuretic agents. The compound(±)-trans-3,4-dichloro-N-methyl-N-2-(1-pyrrolidinyl)cyclohexyl!-benzeneacetamide has been evaluated forits selectivity as an amino acid antagonist C. G. Parsons et al,Neuropharm., 25 (2), 217-220 (1986)!. This same compound has beenevaluated for its neuroprotective activity against kainate-inducedtoxicity W. Lason et al, Brain Res., 452, 333-339 (1989)!. U.S. Pat. No.4,801,604 to Vonvoightlander et al describes certaincis-N-(2-aminocycloaliphatic)benzamides as anticonvulsants including,specifically, the compound cis-3,4-dichloro-N-methyl-N-2-(1-pyrrolidinyl)cyclohexyl!benzamide. Certain of these transbenzeneacetamide derivatives, such as trans-3,4-dichloro-N-methyl-N-2-(1-pyrrolidinyl)cyclohexyl!-benzeneacetamide, have been described ashighly selective ligands for kappa opioid receptors. The cis isomers of3,4-dichloro-N-methyl-N- 2-(1-pyrrolidinyl)cyclohexyl!-benzeneacetamidewere identified to be potent and selective sigma ligands B. R. de Costaet al, J. Med. Chem., 32(8), 1996-2002 (1989)!. Further structureactivity studies with these compounds resulted in the identification of(+)- and (-)-cis-N-3,4-dichlorophenylethyl!-N-methyl-2-(1-pyrrolidinyl)-cyclohexylamines asextremely potent and selective ligands for the sigma receptor. TheseContreras, P. C.; Ragan, D. M.; Bremer, M. E.; Lanthorn, T. H.; Gray, N.M.; Iyengar, S.; Jacobson, A. E.; Rice, K. C.; de Costa, B. R.:Evaluation of U50488H analogs for antiischemic activity in the gerbil.Brain Res. 1991, 546, 79-82! and related (ethylenediamines) compoundsLong, J. B.; Tortella, F. C.; Rice, K. C.; de Costa B. R.: Selectivesigma ligands protect against dynorphin A-induced spinal cord injury inrats. Soc. Neurosci. Abs., 16, 1122 (1990) abs 461.4! were found to beeffective as protective agents for the damaging effects of ischemia andstroke in two different models of ischemia. See, for example, Long, J.B.; Tortella, F. C.; Rice, K. C.; de Costa B. R.: Selective sigmaligands protect against dynorphin A-induced spinal cord injury in rats.Soc. Neurosci. Abs., 16, 1122 (1990) abs 461.4; Contreras, P. C.; Ragan,D. M.; Bremer, M. E.; Lanthorn, T. H.; Gray, N. M.; Iyengar, S.;Jacobson, A. E.; Rice, K. C.; de Costa, B. R.: Evaluation of U50488Hanalogs for antiischemic activity in the gerbil. Brain Res. 1991, 546,79-82. Since these initial findings, neuroprotective activity has beenidentified among certain other high affinity sigma ligands. It is likelythat the protective effects of these and related compounds is mediatedthrough their interaction with the sigma receptor. Scopes et al., J.Med. Chem., 35, 490-501 (1992) describe certain 2-(alkylamino)methyl!-piperidines. In particular, 1-(3,4-dichlorophenyl)acetyl!-2 (alkylamino)methyl!piperidines aredescribed as having activities as kappa opioid receptor agonists.

BRIEF DESCRIPTION OF THE INVENTION

Treatment of CNS disorders and diseases such as cerebral ischemia,psychotic disorders and convulsions, as well as prevention of neurotoxicdamage and neurodegenerative diseases, may be accomplished byadministration of a therapeutically-effective amount of a compound ofthe formula: ##STR2## wherein each of R¹, R⁴, R⁵, R⁶ and R⁷ isindependently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl,aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy,carboxyalkyl, alkanoyl, alkenyl and alkynyl;

wherein each of R², R3 and R⁸ through R¹³ is independently selected fromhydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl,alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano,amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl,alkenyl and alkynyl; wherein R² and R³ may be taken together to form oxoor to form a saturated or partially unsaturated carbocyclic group havingthree to eight ring carbons; wherein R⁴ and R⁵ may be taken together toform a saturated or partially unsaturated carbocyclic group having threeto eight Ting carbons; wherein R⁸ and R⁹ may be taken together to formoxo; wherein R¹⁰ and R¹¹ may be taken together to form oxo; wherein m isan integer from 2-4 and n and p are integers of from one to four;

wherein Z is selected from ##STR3## wherein R¹⁴ may be selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,alkanoyl aralkanoyl, aroyl, aminoalkyl, monoalkylaminoalkyl anddialkylaminoalkyl; wherein each of R¹⁵ and R¹⁶ is independently selectedfrom hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl,aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl,halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyland alkanoyl; wherein each of R¹⁷ and R¹⁸ is independently selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, alkoxyalkyl,haloalkyl, hydroxyalkyl, halo, cyano, carboxy, carboxyalkyl andalkanoyl; wherein A is selected from aryl, heteroaryl, aryloxy,heteroaryloxyl aralkoxy, heteroaralkoxy, arylamino, heteroarylamino,aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthioand heteroaralkylthio; wherein any of the foregoing A groups can befurther substituted with one or more substituents independently selectedfrom hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl,aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, halo, haloalkyl,hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy,carboxyalkyl, alkanoyl, alkenyl and alkynyl; or apharmaceutically-acceptable salt thereof.

A preferred family of compounds of Formula I consists of those compoundswherein each of R¹ R⁴, R⁵, R⁶ and R⁷ is independently selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl,haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl andalkynyl; wherein each of R², R³ and R⁸ through R¹³ is independentlyselected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl,aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl,hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy,carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein R² and R³ may betaken together to form oxo or to form a saturated or partiallyunsaturated carbocyclic group having three to eight ring carbons;wherein R⁴ and R⁵ may be taken together to form oxo or to form asaturated or partially unsaturated carbocyclic group having three toeight ring carbons; wherein R¹⁰ and R¹¹ may be taken together to formoxo; wherein m is an integer from 2-4 and n and p are integers of fromone to four;

wherein Z is selected from ##STR4## wherein R¹⁴ may be selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,alkanoyl, aralkanoyl and aroyl; wherein each of R¹⁵ through R¹⁸ isindependently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl,aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano,carboxy, carboxyalkyl and alkanoyl; wherein A is selected from aryl,heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino,heteroarylamino, aralkylamino, heteroaralkylamino, arylthio,heteroarylthio, aralkylthio and heteroaralkylthio; wherein any of theforegoing A groups can be further substituted with one or moresubstituents independently selected from hydrido, hydroxy, alkyl,cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy,alkoxyalkyl, halo, haloalkyl, hydroxyalkyl, cyano, amino,monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyland alkynyl; or a pharmaceutically acceptable salt thereof.

A more preferred family of compounds within Formula I consists of thosecompounds wherein each of R¹, R⁴, R⁵, R⁶ and R⁷ is independentlyselected from hydrido, loweralkyl, cycloalkyl of three to about eightcarbon atoms, phenylloweralkyl, phenyl, loweralkoxyloweralkyl,haloloweralkyl; hydroxyloweralkyl, carboxy, carboxyloweralkyl,loweralkanyl, loweralkenyl, loweralkynyl; wherein R², R³ and R⁸ throughR¹³ is independently selected from hydrido, hydroxy, loweralkyl,cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of fourto about eight carbon atoms, phenylloweralkyl, phenyl, loweralkoxy,phenoxy, phenylloweralkoxy, loweralkoxyloweralkyl, haloloweralkyl,hydroxyloweralkyl, cyano, amino, monoloweralkylamino, diloweralkylamino,carboxy, carboxyloweralkyl, loweralkanoyl, loweralkenyl andloweralkynyl; wherein R² and R³ may be taken together to form asaturated or partially unsaturated carbocyclic group having three toeight ring carbons; wherein R⁴ and R⁵ may be taken together to form asaturated or partially unsaturated carbocyclic group having three toeight ring carbons; wherein R¹⁰ and R¹¹ may be taken together to formoxo; wherein m is an integer from 2-4 and n and p are integers of fromone to four;

wherein Z is selected from ##STR5## wherein R¹⁴ may be selected fromhydrido, loweralkyl, cycloalkyl of three to about eight carbon atoms,cycloalkylalkyl of four to about eight carbon atoms, phenyl,phenylloweralkyl, heteroaryl, loweralkanoyl, phenylalkanoyl, benzoyl,aminoloweralkyl, monoloweralkyl-aminoloweralkyl anddiloweralkylamino-loweralkyl; wherein each of R¹⁵ and R¹⁶ isindependently selected from hydrido, hydroxy, loweralkyl, cycloalkyl ofthree to about eight carbon atoms, cycloalkylalkyl of four to abouteight carbon atoms, phenyloweralkyl, phenyl, loweralkoxyloweralkyl,haloloweralkyl, hydroxyloweralkyl, halo, cyano, amino,monoloweralkylamino, diloweralkylamino, carboxy, carboxyloweralkyl andloweralkanoyl; wherein each of R¹⁷ and R¹⁸ is independently selectedfrom hydrido, loweralkyl, cycloalkyl of three to about eight carbonatoms, cycloalkylalkyl of four to about eight carbon atoms,phenylloweralkyl, phenyl, loweralkoxyloweralkyl, haloloweralkyl,hydroxyloweralkyl, halo, cyano, carboxy, carboxyloweralkyl andloweralkanoyl; wherein A is selected from phenyl, naphthyl, heteroaryl,phenoxy, naphthyloxy, heteroaryloxy, phenylloweralkoxy,naphthylloweralkoxy, heteroarylloweralkoxy, phenylamino, naphthylamino,heteroarylamino, phenylloweralkylamino, naphthylloweralkylamino,heteroaralkylamino, phenylthio, naphthylthio, heteroarylthio,phenylloweralkylthio and heteroarylloweralkylthio; wherein any of theforegoing A groups can be further substituted with one or moresubstituents independently selected from hydrido, hydroxy, loweralkyl,cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of fourto about eight carbon atoms, phenylloweralkyl, phenyl, loweralkoxy,phenoxy, phenyloweralkoxy, loweralkoxyloweralkyl, halo, haloloweralkyl,hydroxyloweralkyl, cyano, amino, monoloweralkylamino, diloweralkylamino,carboxy, carboxyloweralkyl, loweralkanoyl, loweralkenyl andloweralkynyl; or a pharmaceutically acceptable salt thereof.

A more highly preferred family of compounds of Formula I consists ofthose compounds wherein each of R¹, R⁴, R⁵, R⁶ and R⁷ is independentlyselected from hydrido, loweralkyl, cycloalkyl of three to about eightcarbon atoms, cycloalkylalkyl of four to about eight carbon atoms,benzyl, phenyl, loweralkoxyloweralkyl, haloloweralkyl,hydroxyloweralkyl, loweralkanoyl, loweralkenyl, and loweralkynyl;wherein R², R³ and R⁸ through R¹³ is independently selected fromhydrido, hydroxy, loweralkyl, cycloalkyl of three to about eight carbonatoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl,phenyl, loweralkoxy, phenoxy, benzyloxy, loweralkoxyloweralkyl,haloloweralkyl, hydroxyloweralkyl, loweralkanoyl, loweralkenyl andloweralkynyl; wherein R² and R³ may be taken together to form asaturated or partially unsaturated carbocyclic group having three toeight ring carbons; wherein R⁴ and R⁵ may be taken together to form asaturated or partially unsaturated carbocyclic group having three toeight ring carbons; wherein R¹⁰ and R¹¹ may be taken together to formoxo; wherein m is an integer from 2-4 and n and p are integers of fromone to four;

wherein Z is selected from ##STR6## wherein R¹⁴ may be selected fromhydrido, loweralkyl, cycloalkyl of three to about eight carbon atoms,cycloalkylalkyl of four to about eight carbon atoms, phenyl and benzyl;wherein each of R¹⁵ through R¹⁸ is independently selected from hydrido,loweralkyl, cycloalkyl of three to about eight carbon atoms,cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl,loweralkoxyloweralkyl, hydroxyloweralkyl and halo; wherein A is selectedfrom phenyl, naphthyl, benzo b!thienyl, thienyl, phenoxy, benzyloxy,naphthyloxy, thiophenoxy, phenylamino, benzylamino, naphthylamino,phenylthio, benzylthio and naphthylthio; wherein any of the foregoing Agroups can be further substituted with one or more substituentsindependently selected from hydrido, hydroxy, loweralkyl, cycloalkyl ofthree to about eight carbon atoms, cycloalkylalkyl of four to abouteight carbon atoms, loweralkoxy, loweralkoxyloweralkyl, halo,haloloweralkyl, hydroxyloweralkyl, amino, monoloweralkylamino,diloweralkylamino, loweralkanoyl, loweralkenyl and loweralkynyl; or apharmaceutically acceptable salt thereof.

A family of compounds of particular interest within Formula I arecompounds embraced by Formula II: ##STR7## wherein each of R¹, R⁴, R⁵,R⁶ and R⁷ is independently selected from hydrido, loweralkyl, benzyl andhaloloweralkyl; wherein R², R³ and R⁸ through R¹¹ is independentlyselected from hydrido, hydroxy, loweralkyl, benzyl, phenoxy, benzyloxyand haloloweralkyl; wherein n is an integer of from four to six; whereinm is an integer of from two to four; wherein A is selected from phenyl,naphthyl, benzothienyl, benzofuranyl and thienyl; wherein any of theforegoing A groups can be further substituted with one or moresubstituents independently selected from hydrido, hydroxy, loweralkyl,loweralkoxy, halo, haloloweralkyl, amino, monoloweralkylamino anddiloweralkylamino; or a pharmaceutically acceptable salt thereof.

A more preferred family of compounds within Formula II consists ofcompounds wherein each of R¹, R⁴, R⁵, R⁶ and R⁷ is independentlyselected from hydrido, methyl, ethyl, propyl, benzyl, andhaloloweralkyl, wherein R², R³ and R⁸ through R¹¹ is independentlyselected from hydrido, hydroxy, methyl, ethyl, propyl, benzyl, phenoxy,benzyloxy and haloloweralkyl; wherein n is a number selected from 4 or5; wherein m is an integer of from two or three; wherein A is phenyl ornaphthyl; wherein any of the foregoing A groups can be furthersubstituted with one or more substituents independently selected fromhydroxy, methyl, ethyl, propyl, methoxy, ethoxy, methylenedioxy, halo,trifluoromethyl, amino, methylamino and dimethylamino; or apharmaceutically acceptable salt thereof.

Of highest interest are the following specific compounds:

2- 2-(3,4-dichlorophenyl)ethyl!-2,5-diazabicyclo 3.0.4!nonane

2- 2-(3-benzothienyl)ethyl!-2,5-diazabicyclo 3.0.4!nonane

2- 2-naphthylethyl!-2,5-diazabicyclo 3.0.4!nonane

2- 2-(3,4-dichlorophenyl)ethyl!-2,5-diazabicyclo 4.0.4!decane

2- 2-(3-benzothienyl)ethyl!-2,5-diazabicyclo 4.0.4!decane

2- 2-naphthylethyl!-2,5-diazabicyclo 4.0.4!decane

The term "hydrido" denotes a single hydrogen atom (H) which may beattached, for example, to an oxygen atom to form hydroxyl group. Wherethe term "alkyl" is used, either alone or within other terms such as"haloalkyl" and "hydroxyalkyl", the term "alkyl" embraces linear orbranched radicals having one to about twenty carbon atoms or,preferably, one to about ten carbon atoms. More preferred alkyl radicalsare "lower alkyl" radicals having one to about five carbon atoms. Theterm "cycloalkyl" embraces cyclic radicals having three to about sixcarbon atoms, such as cyclopropyl and cyclobutyl. The term "haloalkyl"embraces radicals wherein any one or more of the alkyl carbon atoms issubstituted with one or more halo groups, preferable selected frombromo, chloro and fluoro. Specifically embraced by the term "haloalkyl"are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkylgroup, for example, may have either a bromo, a chloro, or a fluoro atomwithin the group. Dihaloalkyl and polyhaloalkyl groups may besubstituted with two or more of the same halo groups, or may have acombination of different halo groups. A dihaloalkyl group, for example,may have two bromo atoms, such as a dibromomethyl group, or two chloroatoms, such as a dichloromethyl group, or one bromo atom and one chloroatom, such as a bromochloromethyl group. An example of a polyhaloalkylis a trifluoromethyl group. The terms "alkylol" and "hydroxyalkyl"embrace linear or branched alkyl groups having one to about ten carbonatoms any one of which may be substituted with one or more hydroxylgroups. The term "alkenyl" embraces linear or branched radicals havingtwo to about twenty carbon atoms, preferably two to about ten carbonatoms, and containing at least one carbon-carbon double bond. The term"alkynyl" embraces linear or branched radicals having two to abouttwenty carbon atoms, preferably two to about ten carbon atoms, andcontaining at least one carbon-carbon triple bond. The terms"cycloalkenyl" and "cycloalkynyl" embrace cyclic radicals having threeto about ten ring carbon atoms including, respectively, one or moredouble or triple bonds involving adjacent ring carbons. The terms"alkoxy" and "alkoxyalkyl" embrace linear or branched oxy-containingradicals each having alkyl portions of one to about ten carbon atoms,such as methoxy group. The "alkoxy" or "alkoxyalkyl" radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide haloalkoxy or haloalkoxyalkyl groups. The term"heteroaryl" embraces aromatic ring systems containing one or two heteroatoms selected from oxygen, nitrogen and sulfur in a ring system havingfive or six ring members, examples of which are thienyl, furanyl,pyridinyl, thiazolyl, pyrimidyl and isoxazolyl including benz-fusedsystems such as benzothienyl, 2-quinolinyl and the like. The term"alkylene chain" describes a chain of two to six methylene (--CH2--)groups which may form a cyclic structure with or without a hetero atomin the cyclic structure.

Specific examples of alkyl groups are methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,iso-pentyl, methyl-butyl, dimethylbutyl and neopentyl. Typical alkenyland alkynyl groups may have one unsaturated bond, such as an allylgroup, or may have a plurality of unsaturated bonds, with such pluralityof bonds either adjacent, such as allene-type structures, or inconjugation, or separated by several saturated carbons.

Included within the family of compounds of Formulas I-II are thetautomeric forms of the described compounds, isomeric forms includingenantiomers and diastereoisomers, and the pharmaceutically-acceptablesalts thereof. The term "pharmaceutically-acceptable salts" embracessalts commonly used to form alkali metal salts and to form additionsalts of free acids or free bases. Since the compounds of Formulas I-IIcontain basic nitrogen atoms, such salts are typically acid additionsalts. The phrase "pharmaceutically-acceptable salts" is not intended toembrace quaternary ammonium salts. The nature of the salt is notcritical, provided that it is pharmaceutically acceptable, and acidswhich may be employed to form salts are, of course, well known to thoseskilled in this art. Examples of acids which may be employed to formpharmaceutically acceptable acid addition salts include such inorganicacids as hydrochloric acid, sulfuric acid and phosphoric acid, and suchorganic acids as maleic acid, succinic acid and citric acid. Otherpharmaceutically acceptable salts include salts with alkali metals oralkaline earth metals, such as sodium, potassium, calcium and magnesium,or with organic bases, such as dicyclohexylamine. All of these salts maybe prepared by conventional means by reacting, for example, theappropriate acid or base with the corresponding compound of FormulasI-II in a suitable solvent (e.g. methanol).

General Synthetic Procedures

Compounds of Formulas I and II may be prepared in accordance with thefollowing generic procedures, within which specific schemes are shownfor Formula II type compounds. ##STR8## wherein R¹, R¹⁰ through R¹¹, andn are as defined previously; and wherein B represents a protecting groupsuch as acetyl, benzoyl, t-butyloxycarbonyl or benzyloxycarbonyl.

A process for preparing the compounds of the invention starts withcarboxylic acid derivatives of cycloaminoalkyl compounds of generalstructure 1 where R¹, R¹⁰ through R¹¹, and n have the value assignedpreviously. Examples of compounds within the general structure 1 are theenantiomers of proline (2-pyrrolidinecarboxylic acid) and2-piperidinecarboxylic acid. The amino group of 1 is protected employingprotecting groups such as acetyl, benzoyl, t-butoxycarbonyl orbenzyloxycarbonyl or other amino protecting groups familiar to thoseskilled in the art. This protection can be achieved by reacting theprotecting group as the chloride or anhydride in organic solvents and attemperatures ranging from -60° to reflux of the reaction mixture.##STR9## wherein B, R¹, R⁸, R⁹, R¹⁰, R¹¹, n, and m are as definedpreviously, and R is a carboxyl protecting group, e.g. R is methyl.

In the second step of the process, compounds of the general structure 2are coupled by way of the carboxylic acid group to a carboxy-protectedamino acid of the formula: ##STR10## Examples of amino acids includeglycine, t-butyl glycine, β-amino butyric acid and the like. Thecompounds can be combined neat or in a variety of solvents such astetrahydrofuran. Following isolation of 3, the protecting group B isremoved by methods well known to those skilled in the art. The aminoprotecting group B is removed by mixing 3 with a suitable acid such astrifluoroacetic acid, hydrochloric acid, and the like which are familiarto those skilled in the art. Alternatively, the amino protecting groupis removed by mixing 3 with a suitable base such as sodium hydroxide,potassium hydroxide and the like, which are familiar to those skilled inthe art. The compounds are mixed in a suitable solvent, preferably aprotic solvent such as water, ethylene glycol, or methanol.Alternatively, in the case of the benzyloxycarbonyl group, deprotectioncan be achieved by catalytic hydrogenation in the presence of a suitablecatalyst such as 10% palladium on carbon in a suitable solvent such asmethanol. The temperature of the reaction can vary from room temperatureto reflux of the reaction mixture. For example, treatment of a stirredmixture of 2, a methyl ester hydrochloride of an α-amino acid (1.0 molarequivalent), 1-(dimethylaminopropyl)-3-(ethyl)carbodiimide hydrochloride(1.2 molar equivalents) and N-hydroxybenzotriazole (1 molar equivalents)with triethylamine (2 molar equivalents) afforded 3. This was isolatedby standard methods familiar to those skilled in the art. The product 3was dissolved in trifluoroacetic acid and the solution was stirred forone hour. The product 4 was isolated by evaporation of thetrifluoroacetic acid in vacuo. The temperature of the reaction can varyfrom room temperature to reflux of the reaction mixture. ##STR11##wherein R¹ R⁸, R⁹, R¹⁰, R¹¹ and m and n are as defined previously. Inthe third step of the process, compounds of general structure 4 arecyclized to bicyclic compounds of general structure 5 by dissolvingtrifluoroacetic acid salts of general structure 4 in methanol, treatingwith triethylamine and refluxing the mixture until the cyclization iscomplete. The resulting product 5 is a diketo diazabicycloalkane.

Step 4 ##STR12##

wherein R¹, R⁸, R⁹, R¹⁰, R¹¹, m, and n are as defined previously.

In the fourth step of the process, the diketo diazabicycloalkanes ofgeneral structure 5 are reduced to diazabicycloalkanes of generalstructure 6 by reducing the amide moieties. The reduction can beaccomplished by employing reducing agents well known to those skilled inthe art, such as, for example, employing lithium aluminum hydride,aluminum hydride, sodium borohydride. The reaction can be conductedin-either protic or aprotic solvents, depending on the reducing agent ofchoice. The temperature of the reaction can vary from room temperatureto reflux of the reaction mixture. ##STR13## wherein A, R¹, R², R³, R⁸through R¹¹, m and n are as defined previously; and wherein L¹ is a goodleaving group such as chloro, bromo, acyloxy, or "activated" hydroxy. Inthe fifth step of the process, diazabicycloalkanes of general structure6 are converted to amides of general structure 8 where A, R², and R³have the value assigned previously and L¹ is a good leaving group suchas chloro, bromo, acyloxy, or "activated" hydroxy. The conversion can bebest achieved by mixing the reagents neat or in a protic solvent such astetrahydrofuran, methylene chloride, or ether in the presence of a basesuch as triethylamine. The reaction can be run in the absence orpresence of an activating agent such as dicyclohexylcarbodiimide orphosphorus oxychloride, depending on the leaving group of choice. Thetemperature of the reaction can vary from 0° to reflux of the reactionmixture. ##STR14## wherein A, R¹, R², R³, R⁸ through R¹¹, m and n are asdefined previously.

In the sixth step of the process, amides of general structure 8 areconverted to amines of general structure 9 by employing reducing agentssuch as lithium aluminum hydride, aluminum hydride, sodium borohydride,sodium cyanoborohydride, or other reducing agents familiar to thoseskilled in the art. This reduction can be accomplished in either proticor aprotic solvents, depending on the reducing agent of choice, and attemperatures ranging from room temperature to reflux of the reactionmixture.

Step 60(b)

Alternately, amines of general structure 11 can be prepared according tothe following generic procedure. ##STR15## wherein A, R¹ through R¹¹ andm and n are as defined previously; and wherein L² is a good leavinggroup such as halogen, tosylate, mesylate, or brosylate.

Amines of general structure 11 can be alternately prepared by combiningcompounds of general structure 6 with compounds of general structure 10where A, R¹ through R¹¹, m and n have the values assigned previously andwhere L² is a good leaving group such as halogen, tosylate, mesylate, orbrosylate. The compounds can be combined in a variety of solvents suchas toluene, xylenes, dimethylformamide, hexamethylphosphoramide, orethanol. The temperature of the reaction can vary from room temperatureto reflux of the reaction mixture. ##STR16##

The schemes set forth below illustrate in more detail the above generalmethod for preparing aralkyl diazabicycloalkanes of the presentinvention. ##STR17##

a: 1-(dimethylaminopropyl)-3-(ethyl)carbodiimide·hydrochloride, HOBT,glycine methyl ester, Et₃ N, r.t.; b: CF₃ COOH; c: MeOH, Et₃ N, reflux;d: LiAlH₄, THF, reflux; e: 3,4-dichlorophenylacetic acid, DCC, CH₂ Cl₂,r.t.; f: AlH₃ THF, r.t.

The following Examples are detailed descriptions of the methods ofpreparation of compounds of Formula I. These detailed preparations fallwithin the scope of, and serve to exemplify, the above described GenericProcedures which form part of the invention. These Examples arepresented for illustrative purposes only and are not intended as arestriction on the scope of the invention. All parts are by weightunless otherwise indicated. Most of the commercially available startingmaterials were obtained from Aldrich Chemical Company, Milwaukee, Wis.

Melting points were determined on a Thomas-Hoover capillary apparatusand are uncorrected. Specific rotation determinations at the sodium-Dline were obtained in a 1 dM cell using a Perkin-Elmer 241-MCpolarimeter. Elemental analyses were performed at Atlantic Microlabs,Atlanta, Ga. Chemical-ionization mass spectra (CIMS) were obtained usinga Finnigan 1015 mass spectrometer. Electron ionization mass spectra(EIMS) and high resolution mass measurements (HRMS) were obtained usinga VG-Micro Mass 7070F mass spectrometer. ¹ H-NMR spectra were measuredfrom CDCl₃ solutions using a Varian SL-300 spectrometer. Thin layerchromatography (TLC) was performed on 250 μM Analtech GHLF silica gelplates. TLC system A corresponds to CHCl₃ -MeOH-conc. aq. NH₃ (90:9:1).TLC system B corresponds to CHCl₃ -MeOH-conc. aq. NH₃ (80:18:2). TLCsystem C corresponds to EtOAc/hexanes (1:2). No attempt was made tooptimize the yields. For purposes of clarity, enantiomeric compounds areindicated with prefixes indicating absolute configuration and/or thedirection of rotation whereas racemic compounds are shown withoutprefixes.

EXAMPLE 1

Preparation of (S)-Glycine methylester-N-(tertbutoxycarbonyl)prolinamide

To a stirred mixture of Boc-L-proline (5.0 g, 23 mmol), glycine methylester hydrochloride (2.92 g, 23 mmol, 1.0 eq),1-(dimethyl-aminopropyl)-3-(ethyl)carbodiimide hydrochloride (5.34 g,27.9 mmol, 1.2 eq) and HOBT (3.77 g, 33.5 mmol, 1 eq) was added Et₃ N(6.5 mL, 47 mmol, 2.0 eq) and the reaction mixture was stirred for 24 hat rt when TLC (solvent system C) indicated the reaction to be complete.The solvent was evaporated in vacuo and the residue was taken up inEtOAc (200 mL) and washed successively with water (200 mL), 5% aqueouscitric acid (4×60 mL), 10% aqueous K₂ CO3 (2×100 mL) and the solvent wasevaporated in vacuo to give the product as a colorless crystalline solid(3.89 g): mp 70°-71° C. (EtOAc/isooctane 1:3); ¹ H-NMR (CDCl₃) σ6.54 (brs, 1H, CONH), 4.05 (m, 2H), 3.75 (s, 3H), 3.46 (m, 2H), 2.06-2.44 (m,2H), 1.91 (m, 3H), 1.47 (s, 9H, tBu); Anal (calcd for C₁₃ H₂₂ N₂ O₅): C54.53, H 7.74, N 9.78. Found: C 54.56, H 7.77, N 9.80.

EXAMPLE 2

Preparation of (S)-(Glycine methyl ester)prolinamide

The title compound of Example 1 (2.6 g, 9.1 mmol) was dissolved in CF₃COOH (10 mL) and the solution was stirred at rt for 1 h when TLC(solvent system A) indicated the reaction to be complete. The reactionsolvent was evaporated in vacuo to give a colorless oil (quantitative).Conditions were maintained sufficiently cold (4° C.) and the base wasisolated by partitioning between cold saturated K₂ CO₃ solution andCHCl₃. The product was sufficiently stable for analysis by ¹ H-NMRspectroscopy. For purposes of further characterization, the oxalate saltwas crystallized from 2-propanol: mp 119°-120° C.; ¹ H-NMR (CDCl₃) σ8.09 (br s, 1H, CONH), 4.04 (d, J=5.9 Hz, 2H), 3.78 (dd, J=5.1, 9.0 Hz,1H), 3.75 (s, 3H), 2.90-3.08 (m, 2H), 2.07-2.21 (m, 1H), 1.89-2.01 (m,1H), 1.61-1.83 (m, 2H), 1.63 (br s, 1H, NH); Anal (calcd for C₁₀ H₁₆ N₂O₇): C 43.48, H 5.84, N 10.14. Found: C 43.63, H 5,55, N 9.97.

EXAMPLE 3

Preparation of (S)-1,4-Diketo-2,5-diazabicyclo 3.0.4!nonane

The CF₃ COOH salt of the title compound of Example 2 was dissolved inMeOH (50 mL) and treated with Et₃ N (5.0 mL). The reaction mixture wasboiled under reflux overnight or until complete by TLC (solvent systemA). The solvent was evaporated in vacuo and the oily residue wasdissolved in hot 2-propanol (20 mL). Crystallization occurredspontaneously on cooling to rt to give the desired product (0.91 g,65%): mp 211°-213 ° C.; ¹ H-NMR (CDCl₃) σ 6.41 (br s, 1H, NH), 4.10 (d,J_(gem) =16 Hz, 2H), 3.89 (dd, J_(gem) =17 Hz, J=4.4 Hz, 1H), 3.51-3.71(complex m, 2H), 2.39 (m, 1H), 1.82-2.17 (complex m, 3H); Anal (calcdfor C₇ H₁₀ N₂ O₃): C 54.54, H 6.54, N 18.17. Found: C 54.73, H 6.47, N18.26.

EXAMPLE 4

Preparation of (S)-2,5-Diazabicyclo 3.0.4!nonane

The title compound of Example 3 (0.91 g) in dry THF was added dropwiseat ambient temperature to a stirred solution of LiAlH₄ in THF (24 mL ofa 1.0M solution, 24 mmol). The reaction mixture was stirred at ambienttemperature and then treated dropwise with water (0.9 mL), 15% aqueousNaOH (0.9 mL), and finally water (2.7 mL). The mixture was stirred for 1h and filtered. The filter-cake was washed with a little cold THF (10mL) and the combined filtrate and washings were evaporated in vacuo togive the desired product as a colorless oil. Treatment of a solution ofthe base in EtOH/2-propanol (1:1) with 48% HBr gave the HBr salt (1.04g, 67%) as colorless crystals: mp 234-236; ¹ H-NMR (CDCl₃) σ 2.92-3.16(complex m, 4H), 2.84 (m, 1H), 2.48 (m, 1H), 2.06-2.18 (m, 2H),1.64-1.90 (complex m, 4H), 1.24-1.45 (m, 1H); Anal (calcd for C₇ H₁₆ Br₂N₂): C 29.19, H 5.60, N 9.73. Found: C 29.29, H 5.54, N 9.66.

EXAMPLE 5

Preparation of (S)-2-(3,4-Dichlorophenylacetyl)-2,5-diazabicyclo3.0.4!nonane.

The HBr salt of the title product of Example 4 (1.00 g, 3.3 mmol) and3,4-dichlorophenylacetic acid (1.07 g, 5.2 mmol, 1.5 eq) and DCC (1.43g, 6.9 mmol, 2.0 eq) were reacted by addition of Et₃ N (2.4 mL, 5.0 eq)to give the title compound (0.84 g, 92%) as a colorless crystallinesolid. The reaction was conducted as follows. To a stirred solution ofthe dichlorophenylacetic acid in CH₂ Cl₂ (100mL) was added a solution ofthe DCC in CH₂ Cl₂ (100 mL) and the solution was stirred for 10 min atrt. To the precipitated complex was added the salt of the title compoundof Example 4 followed by the Et₃ N and stirring was continued until TLC(solvent system A) indicated the reaction to be complete. Theprecipitated DCU was removed by filtration and the filter cake waswashed with Et₂ O (50 mL). The filtrate was diluted with enough Et₂ O torender the organic layer less dense than the aqueous layer, and theorganic extract was then extracted with 10% aqueous citric acid (200 mL)and discarded. The aqueous layer was washed with Et₂ O (2×200 mL) andthe combined washings were discarded. The aqueous layer was basified byaddition of excess concentrated aqueous NH₃ solution and extracted withCH₂ Cl₂ (2×200 mL). The combined organic layer was washed with water,dried (Na₂ SO₄) and evaporated to give the desired product: mp102.5°-103.5° C. (2-propanol); ¹ H-NMR (CDCl₃) σ 7.39 (d, J=7.9 Hz, 1H),7.35 (d, J=2.0 Hz, 1H), 7.09 (d, J=2.0, 7.9 Hz, 1H), 4.67 (dd, J_(gem)=39 Hz, J=13 Hz, 1H), 3.81 (dd, J_(gem) =44, J=13 Hz, 1H), 3.68 (d,J=3.8 Hz, 2H), 2.73-3.28 (complex m, 3H), 1.98-2.48 (complex m, 3H),1.64-1.93 (complex m, 4H), 1.32-1.48 (m, 1H); Anal (calcd for C₁₅ H₁₈Cl₂ N₂ O): C 57.52, H 5.79, N 8.94. Found: 57.60, H 5.76, N 8.94.

EXAMPLE 6

Preparation of (S)-2- 2-(3,4-Dichlorophenyl)ethyl!-2,5-diazabicyclo3.0.4!nonane

The title compound of Example 5 (0.5 g, 1.60 mmol) was reduced with0.667 M Al_(H) ₃ in THF (12 mL, 8.0 mmol, 5 eq) by adding the Example 5title compound dropwise to freshly prepared AlH₃ solution. TLC (solventsystem A) indicated the reaction to be complete after 20 min at rt. Thereaction mixture was poured into 15% aqueous NaOH (100 mL) and thesolution was extracted with CHCl₃ (200 mL). The organic layer was driedby filtration through a column of Na₂ SO₄ and the solvent was evaporatedin vacuo to give the title compound as a colorless oil. The HBr saltcrystallized from EtOH (0.50 g, 68%): mp 261.5°-262.5° C. (dec); ¹ H-NMR(CDCl₃) σ 7.34 (d, J=8.3 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.04 (dd,J=2.0, 8.3 Hz, 1H), 3.00-3.12 (complex m, 3H), 2.89 (dm, J=7.8 Hz, 1H),2.73-2.81 (m, 2H), 2.58-2.67 (m, 2H), 2.30 (d, J=7.6 Hz, 2H), 2.00-2.22(complex m, 2H), 1.68-1.98 (complex m, 4H), 1.42 (m, 1H); Anal (calcdfor C₁₅ H₂₂ Br₂ Cl₂ N₂ : C 39.08, H 4.81, N 6.08. Found: C 39.16, H4.76, N 5.98.

EXAMPLE 7

Preparation of (R)-Glycine methylester-N-(tert-butoxycarbonyl)prolinamide

The title compound was synthesized as described above in Example 1 forits enantiomer starting with Boc-D-proline (5.0 G, 23 mmol) to give 2.39g of thereof as a colorless crystalline solid identical to the titlecompound of Example 1: mp 70°-71° C.; Anal (calcd for C₁₃ H₂₂ N₂ O₅): C4.53, H 7.74, N 9.78. Found: C 54.42, H 7.73, N 9.84.

EXAMPLE 8

Preparation of Glycine methyl esterprolinamide

The title compound of Example 7 (2.00 G) was converted to the CF₃ COOHsalt of the N-deprotected product (quantitative) as described above forits enantiomer. For the purposes of further characterization, theoxalate salt was crystallized from 2-propanol: mp 119°-120° C. The ¹H-NMR (CDCl₃) was identical to that of S-30 above. Anal (calcd for C₁₀H₁₆ N₂ O₇): C 43.48, H 5.84, N 10.14. Found: C 54.67, H 6.58, N 18.18.

EXAMPLE 9

Preparation of (R) -1,4 -Diketo-2,5 -diazabicyclo- 3.0.4!nonane

The CF₃ COOH salt of the title compound of Example 8 was cyclized asdescribed above for its enantiomer to give 0.68g, 64% of product mp211°C.; ¹ H-NMR (CDCl₃) identical to its enantiomer above; Anal (calcd forC₇ H₁₀ N₂ O₂): C 54.54, H 6.54, N 18.17. Found: C 54.67, H6.58, N 18.18.

EXAMPLE 10

Preparation of (R)-2,5-Diazabicyclo 3.0.4!nonane

The product of Example 9 (0.50 g) was reduced with 15 mL of a 1.0MLiAlH₄ in THF as described in Example 4 to give 0.63 g, 68% of thedesired product: mp 234°-236° C. (MeOH); ¹ H-NMR (CDCl₃) identical toits enantiomer; Anal (calcd for C₇ H₁₆ Br₂ N₂): C 29.19, H 5.60, N 9.73.Found: C 29.25, H 5.61, N 9.69

EXAMPLE 11

Preparation of (R)-(3,4-Dichlorophenylacetyl)-2,5-diazabicyclo3.0.4!nonane

The HBR salt of the title compound of Example 10 (0.50 g) was coupledwith 3,4-dichlorophenylacetic acid as described in Example 5 to give thedesired product (0.51 g, 94%): mp 101°-102° C. (2-propanol); ¹ H-NMR(CDCl₃) identical to its enantiomer above; Anal (calcd for C₁₅ H₁₈ Cl₂N₂ O): C 57.52, H 5.79, N 8.94. Found: C 57.53, H 5.81, N 8.89.

EXAMPLE 12

Preparation of (R)-2- 2-(3,4-Dichlorophenyl)ethyl!-2,5-diazabicyclo3.0.4!nonane

The title compound of Example 11 (0.425 g) was reduced with 0.667M AlH₃in THF as described in Example 6 above to give the HBr salt of the titlecompound 0.30 g (48%): mp 263°-265° C. (EtOH); ¹ H-NMR (CDCl₃) identicalto its enantiomer above; Anal (calcd for C₁₅ H₂₂ Br₂ Cl₂ N₂): C 39.08, H4.81, N 6.08. Found: C 39.17, H 4.78, N 6.05.

EXAMPLE 13

Preparation of Glycine methyl ester-N-(butoxycarbonyl)pipecolinamide

1-(tertButoxycarbonyl)-2-piperidinecarboxylic acid (11.46 g, 1.2 eq),glycine methyl ester hydrochloride (9.42 g),1-(dimethylaminopropyl)-3-(ethyl)carbodiimide hydrochloride (8.00 g, 1.0eq) and Et₃ N (16.3 mL) were reacted as described in Example 1 to give5.6 g of the title compound as a colorless crystalline solid: mp118.5°-119.5° C. (EtOAc/isooctane 1:3); ¹ H-NMR (CDCl₃) σ 6.60 (br s,1H, CONH), 4.81 (m, 1H), 3.82-4.35 (complex m, 4H), 3.76 (s, 3H, OMe),2.89 (m, 1H), 2.32 (m, 1H), 1.33-1.72 (complex m, 4H), 1.49 (s, 9H,tBu); Anal (calcd for C₁₄ H₂₄ N₂ O₅): C 55.99, H 8.05, N 9.33. Found: C56.00, H 8.09, N 9.36.

EXAMPLE 14

Preparation of 1,4-Diketo-2,5-diazabicyclo- 4.0.4!decane

The title compound of Example 13 (4.60 g) was dissoved in CF₃ COOH andthe solution stirred at rt for 10 min. The solvent was evaporated togive the corresponding N-deprotected amine CF₃ COOH salt (quantitative).This salt was dissolved in saturated NaHCO₃ (50 mL) and the solution wasextracted with CHCl₃ (4×200 mL). The combined organic extract was dried(Na₂ SO₄) and the solvent was evaporated in vacuo at rt to give anintermediate as a colorless oil in quantitative yield. For purposes offurther characterization, the fumarate of this intermediate wascrystallized from EtOAc: mp 116°-118° C.; ¹ H-NMR (CDCl₃) σ 7.29 (br s,1H, NHCO), 4.05 (d. J=5.6 Hz, 2H), 3.76 (s, 3H, COOMe), 3.26 (m,, 1H),3.06 (dm, Jgem=12 Hz, 1H), 2.70 (m, 1H), 1.97 (m, 1H), 1.80 (m, 1H),1.33-1.67 (complex m, 5H); Anal (calcd for C₁₃ H₂₀ N₂ O₇): C 49.36, H6.37, N 8.86. Found: C 49.22, 146.41, N 8.85. The fumarate was found tobe indefinitely stable unlike its free base. The free base as obtainedabove was dissolved in MeOH (50 mL) and the solution was boiled underreflux overnight under an argon atmosphere. Evaporation of the solventin vacuo afforded the desired product as a colorless crystalline solid(quantitative). Crystallization from 2-propanol afforded the titlecompound as colorless crystals: mp 159°-160° C.; ¹ H-NMR (CDCl₃) σ 6.11(br s, 1H, NH), 4.70 (dm, J_(gem) =13 Hz, 1H), 4.05 (br s, 2H), 3.85(dm, J_(gem) =11 Hz, 1H), 2.53(m, 1H), 2.36 (m, 1H), 2.02 (m, 1H),1.40-1.68 (complex m, 3H); Anal (calcd for C₈ H₁₂ N₂ O₂): C 57.13, H7.19 , N 16.66. Found: C 57.23, H 7.17, N 16.70.

EXAMPLE 15

Preparation of 2,5-Diazabicyclo 4.0.4!decane

The title compound of Example 14 (0.80 g) was reduced with 1.0M LiAlH₄in THF as described in Example 4 to give the desired product (0.63 g,94%) as a clear colorless oil. The oxalate salt was crystallized fromMeOH: mp 178°-179° C. (dec); ¹ H-NMR (CDCl₃) σ 2.94 (m, 2H), 2.75-2.84(m, 2H), 2.72 (dm, J=11 Hz, 1H), 2.50 (dd, J=10, 12 Hz, 1H), 2.00-2.20(complex m, 2H), 1.71-1.89 (complex m, 2H), 1.54-1.69 (complex m, 3H),1.49 (m, 1H), 1.11-1.38 (complex m, 2H); Anal (calcd for C₁₂ H₂₀ N₂ O₈):C 44.98, H 6.29, N 8.75. Found: C 45.11, H 6.31, N 8.80.

EXAMPLE 16

Preparation of 2-(3,4-Dichlorophenylacetyl)-2,5-diazabicyclo4.0.4!decane

The title compound of Example 15 base (0.49 g, 3.5 mmol) was coupledwith 3,4-dichlorophenylacetic acid (1.07 g, 5.2 mmol) as described inExample 5 to give the amide as a crystalline solid: mp 119°-120° C.(2-propanol); ¹ H-NMR (CDCl₃) σ 7.39 (d, J=8.3 Hz, 1H), 7.35 (d, J=2.0Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 4.48 (m, 1H), 3.66 (br s, 2H), 3.64 (m,1H), 3.29 and 2.87 (m, 1H), 2.64-2.85 (complex m, 2H), 2.41 and 2.09 (m,1H), 1.93-2.06 (complex m, 2H), 1.40-1.87 (complex m, 5H), 1.12-1.36(complex m, 2H); Anal (calcd for C₁₆ H₂₀ Cl₂ N₂ O): C 58.72, H 6.16, N8.56. Found: C 58.80, H 6.17, N 8.52.

EXAMPLE 17

Preparation of 2- 2-(3,4-Dichlorophenyl)ethyl!-2,5-diazabicyclo4.0.4!decane

The amide prepared in Example 16 (0.50 g) was reduced with 0.66 M AlH₃in THF (11.6 mL) as described forin to Example 6 give the HBr salt ofthe title compound (0.5 g, 69%): mp 272°-273° C. (dec) (EtOH); ¹ H-NMR(CDCl₃) s 7.34 (d, J=8.3 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.04 (dd,J=2.0, 8.3 Hz, 1H), 2.81-2.91 (m, 2H), 2.75 (m, 3H), 2.54 (m, 2H), 2.31(d, J=8.3 Hz, 2H), 1.86-2.11 (complex m, 3H), 1.48-1.82 (complex m, 5H),1.16-1.39 (m, 2H); Anal (calcd for C₁₆ H₂₄ Br₂ Cl₂ N₂): C 40.45, H 5.09,N 5.90. Found: C 40.57, H 5.12, N 5.81.

BIOLOGICAL EVALUATION

Radioreceptor Assay

The compounds of Examples 6,12 and 17 were tested for their ability todisplace ³ H!(+)-pentazocine from guinea pig brain membranes de Costa etal, FEBS Lett., 251, 53-58, 1989! to determine the relative potency ofthe compounds interacting with the sigma receptor. Receptor bindingassays were performed using the crude synaptosomal (P₂) membranefraction of guinea pig brain.

Crude P₂ membrane fractions were prepared from frozen (-80° C.) guineapig brains (Pel-Freeze, Rogers, AK), minus cerebella. After removal ofcerebella, brains were allowed to thaw slowly on ice and placed inice-cold 10 mM Tris-HCl, pH 7.4, containing 320 mM sucrose (Tris-sucrosebuffer). Brains were then homogenized in a Potter-Elvehjem homogenizerby 10 strokes of a motor driven Teflon pestle in a volume of 10 mL/gtissue wet weight. The homogenate was centrifuged at 1000g for 10 min at4° C., and the supernatants were saved. The pellets were resuspended byvortexing in 2mL/g ice-cold Tris-sucrose and centrifuged again at 1000 gfor 10 min. The combined 1000 g supernatant was centrifuged at 31000 gfor 15 min at 4° C. The pellets were resuspended by vortexing in 3 mL/gmof 10 mM Tris-HCl, pH 7.4, and the suspension was allowed to incubate at25° C. for 15 min. Following centrifugation at 31000g for 15 min, thepellets were resuspended by gentle Potter-Elvehjem homogenization to afinal volume of 1.53 mL/g in 10 mM Tris-HCl, pH 7.4. Aliquots werestored at -80° C. until use. Protein concentration was determined by themethod of Lowry et al. Lowry et al, J. Biol. Chem., 193, 265-271, 1951!using bovine serum albumin (BSA) as standard.

To prepare rat brain crude P₂ membranes, male Sprague-Dawley rats(150-200 g, Charles River,. Boston, Mass.) were sacrificed bydecapitation. Brains (minus. cerebella) were then treated as describedabove.

Each compound was initially screened at concentrations of 10, 100, and1000 nM in order to obtain an estimate of sigma binding affinity and todetermine the appropriate concentration range to use in 12-pointcompetition curves. For most compounds in the study, a concentrationrange of 0.0005-100 nM was appropriate. A range of 0.005-1000 nM or0.05-10,000 nM was used for the less potent compounds. Twelveconcentrations of unlabeled ligand were incubated with 3 nM ³ H!(+)-pentazocine as described previously de Costa et al, FEBS Lett., 251,53-58, 1989!. The CDATA iterative curve-fitting program (EMF Software,Inc., Baltimore, Md.) was used to determine IC₅₀ values. Values are theaverage of 2-4 experiments±SEM. Each experiment was carried out induplicate. The Cheng-Prussoff equation Cheng, Y. -C. and Prusoff, W. H.,Biochem. Pharmacol., 22, 3099-3108, 1973! was then used to convert IC₅₀values to apparent K_(i) values. The K_(d) for ³ H!-(+)-pentazocine (4.8nM) was determined in independent experiments using guinea pig brainmembranes.

Sigma receptors were labeled with ³ H!-(+)-pentazocine (Specificactivity=51.7 Ci/mmol). Incubations were carried out in 50 mM Tris-HCl,pH 8.0, for 120 min at 25° C. in a volume of 0.5 mL with 500 μg ofmembrane protein and 3 nM ³ H!-(+)-pentazocine. Nonspecific binding wasdetermined in the presence of 10 μM (+)-pentazocine. Assays wereterminated by the addition of 5 mL of ice-cold 10 mM Tris-HCl, pH 8.0,and filtration through glass-fiber filters (Schleicher and Schuell).Filters were then washed twice with 5 mL of ice-cold Tris-HCl buffer.Filters were soaked in. 0.5% polyethylenimine for at least 30 min at 25°C. prior to use.

                  TABLE II                                                        ______________________________________                                                        Ki ( 3H! (+) -Pent)                                           Test Compound   nM                                                            ______________________________________                                        Compound of Ex. 6                                                                             969.83                                                        Compound of Ex. 12                                                                            3.67                                                          Compound of Ex. 17                                                                            0.77                                                          ______________________________________                                    

Also embraced within this invention is a class of pharmaceuticalcompositions comprising one or more compounds of Formula I inassociation with one or more non-toxic, pharmaceutically-acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as "carrier" materials) and, if desired, other activeingredients. The compounds of the present invention may be administeredby any suitable route, preferably in the form a pharmaceuticalcomposition adapted to such a route, and in a dose effective for thetreatment intended. Therapeutically effective doses of the compounds ofthe present invention required to prevent or arrest the progress of themedical condition are readily ascertained by one of ordinary skill inthe art. The compounds and composition may, for example, be administeredintravascularly, intraperitoneally, subcutaneously, intramuscularly ortopically.

For oral administration, the pharmaceutical compositions may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. These may with advantagecontain an amount of active ingredient from about 1 to 250 mg,preferably from about 25 to 150 mg. A suitable daily dose for a mammalmay vary widely depending on the condition of the patient and otherfactors. However, a dose of from about 0.1 to 3000 mg/kg body weight,particularly from about 1 to 100 mg/kg body weight, may be appropriate.

The active ingredient may also be administered by injection as acomposition wherein, for example, saline, dextrose or water may be usedas a suitable carrier. A suitable daily dose is from about 0.1 to 100mg/kg body weight injected per day in multiple doses depending on thedisease being treated. A preferred daily dose would be from about 1 to30 mg/kg body weight. Compounds indicated for prophylactic therapy willpreferably be administered in a daily dose generally in a range fromabout 0.1 mg to about 100 mg per kilogram of body weight per day. A morepreferred dosage will be a range from about 1 mg to about 100 mg perkilogram of body weight. Most preferred is a dosage in a range fromabout 1 to about 50 mg per kilogram of body weight per day. A suitabledose can be administered, in multiple sub-doses per day. These sub-dosesmay be administered in unit dosage forms. Typically, a dose or sub-dosemay contain from about 1 mg to about 100 mg of active compound per unitdosage form. A more preferred dosage will contain from about 2 mg toabout 50 mg of active compound per unit dosage form. Most preferred is adosage form containing from about 3 mg to about 25 mg of active compoundper unit dose.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed may vary widely and thereforemay deviate from the preferred dosage regimen set forth above.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate to the indicated routeof administration. If administered per os, the compounds may be admixedwith lactose, sucrose, starch powder, cellulose esters of alkanoicacids, cellulose alkyl esters, talc, stearic acid; magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, and then tableted or encapsulated forconvenient administration. Such capsules or tablets may contain acontrolled-release formulation as may be provided in a dispersion ofactive compound in hydroxypropylmethyl cellulose. Formulations forparenteral administration may be in the form of aqueous or non-aqueousisotonic sterile injection solutions or suspensions. These solutions andsuspensions may be prepared from sterile powders or granules having oneor more of the carriers or diluents mentioned for use in theformulations for oral administration. The compounds may be dissolved inwater, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, aqueous sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

What is claimed is:
 1. A compound having the formula: ##STR18## wherein:each of R¹, R⁴, R⁵, R⁶ and R⁷ is independently selected from the groupconsisting of hydrido, loweralkyl, benzyl and haloloweralkyl;each of R²,R³, and R⁸ through R¹¹ is independently selected from the groupconsisting of hydrido, hydroxy, loweralkyl, benzyl, phenoxy, benzyloxyand haloloweralkyl; n is an integer of from three to four; m is equal totwo; and A is selected from the group consisting of phenyl, naphthyl,benzothienyl, benzofuranyl and thienyl and wherein any of the foregoingA groups can be further substituted with one or more substituentsindependently selected from the group consisting of hydrido, hydroxy,loweralkyl, loweralkoxy, halo, haloloweralkyl, amino,monoloweralkylamino and diloweralkylamino; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1,wherein:each of R¹, R⁴, R⁵, R⁶ and R⁷ is independently selected from thegroup consisting of hydrido, methyl, ethyl, propyl, benzyl andhaloloweralkyl; each of R², R³ and R⁸ through R¹⁰ are independentlyselected from the group consisting of hydrido, hydroxy, methyl, ethyl,propyl, benzyl, phenoxy, benzyloxy and haloloweralkyl; n is an integerof from three to four; m is equal to two; and A is selected from thegroup consisting of phenyl, napthyl, and benzothienyl and wherein any ofthe foregoing A groups can be further substituted with one or moresubstituents independently selected from the group consisting ofhydrido, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, halo,trifluoromethyl, amino, methylamino and dimethylamino; or apharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition comprising a therapeutically-effective amount of an activecompound for treating or preventing a CNS related disorder selected fromthe group consisting of ischemia or a psychotic disorder, wherein theactive compound has the formula: ##STR19## wherein: each of R¹, R⁴, R⁵,R⁶ and R⁷ is independently selected from the group consisting ofhydrido, loweralkyl, benzyl and haloloweralkyl;each of R², R³, and R⁸through R¹¹ is independently selected from the group consisting ofhydrido, hydroxy, loweralkyl, benzyl, phenoxy, benzyloxy andhaloloweralkyl; n is an integer of from three to four; m is an integerof two; A is selected from the group consisting of phenyl, naphthyl,benzothienyl, benzofuranyl and thienyl and wherein any of the foregoingA groups can be further substituted with one or more substituentsindependently selected from the group consisting of hydrido, hydroxy,loweralkyl, loweralkoxy, halo, haloloweralkyl, amino,monoloweralkylamino and diloweralkylamino; or a pharmaceuticallyacceptable salt thereof.
 4. A composition according to claim 3,wherein:each of R¹, R⁴, R⁵, R⁶ and R⁷ is independently selected from thegroup consisting of hydride, methyl, ethyl, propyl, benzyl andhaloloweralkyl; each of R², R³, and R⁸ through R¹⁰ are independentlyselected from the group consisting of hydride, hydroxy, methyl, ethyl,propyl, benzyl, phenoxy, benzyloxy and haloloweralkyl; n is an integerof from three to four; m is equal to two; and A is selected from thegroup consisting of phenyl, napthyl, and benzothienyl and wherein any ofthe foregoing A groups can be further substituted with one or moresubstituents independently selected from the group consisting ofhydride, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, halo,trifluoromethyl, amine, methylamine and dimethylamino; or apharmaceutically acceptable salt thereof.
 5. A method for treating amammal in need of treatment for a CNS-related disorder selected from thegroup consisting of ischemia or a psychotic disorder, which methodcomprises administering to the patient a therapeutically-effectiveamount of a pharmaceutical composition containing as thetherapeutically-effective component a compound having the formula:##STR20## wherein: each of R¹, R⁴, R⁵, R⁶ and R⁷ is independentlyselected from the group consisting of hydrido, loweralkyl, benzyl andhaloloweralkyl;each of R², R³, and R⁸ through R¹¹ is independentlyselected from the group consisting of hydrido, hydroxy, loweralkyl,benzyl, phenoxy, benzyloxy and haloloweralkyl; n is an integer of fromthree to four; m is an integer of two; A is selected from the groupconsisting of phenyl, naphthyl, benzothienyl, benzofuranyl and thienyland wherein any of the foregoing A groups can be further substitutedwith one or more substituents independently selected from the groupconsisting of hydrido, hydroxy, loweralkyl, loweralkoxy, halo,haloloweralkyl, amino, monoloweralkylamino and diloweralkylamino; or apharmaceutically acceptable salt thereof.
 6. A method according to claim5, wherein:each of R¹, R⁴, R⁵, R⁶ and R⁷ is independently selected fromthe group consisting of hydrido, methyl, ethyl, propyl, benzyl andhaloloweralkyl; each of R², R³, and R⁸ through R¹⁰ are independentlyselected from the group consisting of hydrido, hydroxy, methyl, ethyl,propyl, benzyl, phenoxy, benzyloxy and haloloweralkyl; n is an integerof from three to four; m is equal to two; and A is selected from thegroup consisting of phenyl, napthyl, and benzothienyl and wherein any ofthe foregoing A groups can be further substituted with one or moresubstituents independently selected from the group consisting ofhydrido, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, halo,trifluoromethyl, amino, methylamino and dimethylamino; or apharmaceutically acceptable salt thereof.
 7. The compound of claim 3,selected from the group consisting of2-2-(3,4-dichlorophenyl)ethyl!-2,5-diazabicyclo 3.0.4!nonane, 2-2-(3-benzothienyl)ethyl!-2,5-diazabicyclo 3.0.4!nonane, 2-2-naphthylethyl!-2,5-diazabicyclo 3.0.4!nonane, 2-2-(3,4-dichlorophenyl)ethyl!-2,5-diazabicyclo 4.0.4!decane, 2-2-(3-benzothienyl)ethyl!-2,5-diazabicyclo 4.0.4!decane, and 2-2-naphthylethyl!-2,5-diazabicyclo 4.0.4!decane.
 8. The compound of claim7, which is (S)-2- 2-(3,4-dichlorophenyl)ethyl!-2,5-diazabicyclo3.0.4!nonane.
 9. The compound of claim 7, which is (R)-2-2-(3,4-dichlorophenyl)ethyl!-2,5-diazabicyclo 3.0.4!nonane.
 10. Thecompound of claim 7, which is 2-2-(3,4-dichlorophenyl)ethyl!-2,5-diazabicyclo 4.0.4!decane.
 11. Themethod of claim 6, wherein said compound is selected from the groupconsisting of2- 2-(3,4-dichlorophenyl)ethyl!-2,5-diazabicyclo3.0.4!nonane, 2- 2-(3-benzothienyl)ethyl!-2,5-diazabicyclo 3.0.4!nonane,2- 2-naphthylethyl!-2,5-diazabicyclo 3.0.4!nonane, 2-2-(3,4-dichlorophenyl)ethyl!-2,5-diazabicyclo 4.0.4!decane, 2-2-(3-benzothienyl)ethyl!-2,5-diazabicyclo 4.0.4!decane, and 2-2-naphthylethyl!-2,5-diazabicyclo 4.0.4!decane.
 12. The method of claim11, wherein said compound is (S)-2-2-(3,4-dichlorophenyl)ethyl!-2,5-diazbicyclo 3.0.4!nonane.
 13. Themethod of claim 11, wherein said active compound is (R)-2-2-(3,4-dichlorophenyl)ethyl!-2,5-diazbicyclo 3.0.4!nonane.
 14. Themethod of claim 11, wherein said active compound is 2-2-(3,4-dichlorophenyl)ethyl!-2,5-diazbicyclo 4.0.4!decane.
 15. Themethod of claim 5 wherein said CNS-related disorder is cerebralischemia.
 16. The method of claim 5 wherein said CNS-related disorder isa psychotic disorders.
 17. The composition of claim 4, wherein saidactive compound is selected from the group consisting of2-2-(3,4-dichlorophenyl)ethyl!-2,5-diazabicyclo 3.0.4!nonane, 2-2-(3-benzothienyl)ethyl!-2,5-diazabicyclo 3.0.4!nonane, 2-2-naphthylethyl!-2,5-diazabicyclo 3.0.4!nonane, 2-2-(3,4-dichlorophenyl)ethyl!-2,5-diazabicyclo 4.0.4!decane, 2-2-(3-benzothienyl)ethyl!-2,5-diazabicyclo 4.0.4!decane, and 2-2-naphthylethyl!-2,5-diazabicyclo 4.0.4!decane.
 18. The composition ofclaim 17, wherein said active compound is (S)-2-2-(3,4-dichlorophenyl)ethyl!-2,5-diazbicyclo 3.0.4!nonane.
 19. Thecomposition of claim 17, wherein said active compound is (R)-2-2-(3,4-dichlorophenyl)ethyl!-2,5-diazbicyclo 3.0.4!nonane.
 20. Thecomposition of claim 17, wherein said active compound is 2-2-(3,4-dichlorophenyl)ethyl!-2,5-diazbicyclo 4.0.4!decane.